HIV and SIV induce a slow progressive disease, characterized by the massive loss of memory CD4+ T cells during the acute infection followed by a recovery phase in which virus replication is partially controlled. However, because the initial injury is so severe and virus production persists, the immune system eventually collapses and a symptomatic fatal disease invariably occurs. We have assessed CD4+ T cell dynamics and disease progression in 12 SIV infected rhesus monkeys for more than 2 years. Three macaques exhibiting a rapid progressor (RP) phenotype experienced rapid and irreversible loss of memory, but not naive, CD4+ T lymphocytes from peripheral blood and secondary lymphoid tissues and died within the first six months of virus inoculation. In contrast, SIV infected conventional progressor (CP) animals sustained marked but incomplete depletions of memory CD4+ T cells and continuous activation/proliferation of this T lymphocyte subset. This was associated with a profound loss of naive CD4+ T cells from peripheral blood and secondary lymphoid tissues. At the time of death, virtually no memory CD4+ T lymphocytes were present at effector sites in CP monkeys. These data suggest that the persistent loss of memory CD4+T cells, which are being eliminated by direct virus killing and activation induced cell death, requires the continuous differentiation of naive into memory CD4+ T cells. This unrelenting replenishment process eventually leads to the exhaustion of the naive CD4+T cell pool and the development of disease.[unreadable] [unreadable] During the past 5 to 6 years, highly pathogenic simian-human immunodeficiency viruses (SHIVs), which encode the HIV-1 envelope glycoprotein, have been extensively used as challenge viruses in vaccine experiments carried out in rhesus macaques. We previously reported that unlike HIV and SIV, the commonly used SHIVs enter CD4+ T lymphocytes using the CXCR4 coreceptor, expressed primarily on naive CD4+ T cells. As a consequence, SHIVs frequently cause an unusual clinical syndrome consisting of a rapid, synchronous, and systemic elimination of CD4+ T lymphocytes leading to the early development of clinical disease and death from immunodeficiency at 12 to 30 weeks post virus inoculation. HIV and SIV utilize the CCR5 chemokine coreceptor, expressed exclusively on memory CD4+ T lymphocytes, and rather than causing a rapid-onset disease, are effectively controlled for extended periods of time. During the past year, we have generated two novel SHIVs with properties more like HIV: one carries an envelope glycoprotein that uses the CCR5 coreceptor and targets memory T cells for elimination; the second, unlike currently available SHIVs, bears the HIV Gag, Pol, Vif, and Nef genes, in addition to the HIV Tat, Rev, Vpu, and Env genes and is able to replicate robustly in simian cells due to the insertion of: 1) a 7 amino acid segment from the SIV CA gene and 2) the entire SIV Vif gene. Both SHIVs are presently being tested in pig-tailed macaques and rhesus monkeys for their capacity to cause chronic infections and induce symptomatic disease.